Gastric retention systems are prepared in different ways. Systems that are capable of swelling and being retained in the gastric environment give a feeling of satiety and can be used in controlling appetite and therefore obesity.
Another subject with a vast amount of work on these systems is the control of drug delivery. The control may be spatial, temporal or both. Controlled drug delivery systems deliver drug to the body so as to establish therapeutically effective blood levels of the active ingredient and once these blood levels are achieved they continue to maintain constant blood levels for long durations by delivering the drug to the body at a slow rate. By avoiding peaks and troughs in blood levels associated with conventional dosage forms, controlled drug delivery systems lower the incidence of adverse effects or side effects. Very importantly controlled drug delivery systems reduce the frequency of dosing leading to convenience to the patient in terms of dosing and compliance to the specified dosage regimens.
It is generally known that the rate at which an oral controlled drug delivery system delivers the drug into the gastrointestinal fluids may not the same as the rate at which it releases the drug into a test aqueous fluid because the gastrointestinal fluid's pH, composition and agitation intensity change with the specific location of the drug delivery system in the gastrointestinal tract i.e. from the stomach to the colon, fasted versus fed state, type and amount of food ingested, and also due to variations in these factors from individual to individual. In addition, the drug may not be absorbed in the same manner and propensity as we move from the stomach to the colon. Some drugs have an “absorption window” i.e. they are absorbed only from the upper parts of the gastrointestinal tract, whereas there are others whose absorption from the colon is not uniform or complete. Thus, the location of the controlled drug delivery system in the gastrointestinal tract as well as the rate at which the controlled drug delivery system moves from the stomach to the colon represent important factors that need to be considered in the design of an oral controlled drug delivery system. It is thus known to those skilled in the art that an oral controlled delivery should be designed not only with a control on the rate at which it releases the drug over the drug delivery time period (temporal control) but also a control on the location from which it is delivered (spatial control). The spatial control can be achieved by prolonging the period of retention of the system in the stomach. Gastric retention systems are also beneficial when the drug is effective locally in the stomach. Drugs absorbed in the upper part of the gastrointestinal tract may exhibit variability in absorption due to inter and intra-individual variability in gastric emptying and gastrointestinal motility. This variation in absorption is addressed partly by a gastric retention drug delivery system and may be further addressed by administering a dosage form comprising the drug such that a part of the drug is available as immediate release, and a part is available as sustained or controlled release.
One of the approaches that has been used for achieving spatial control involves increasing the gastric retention of sustained or controlled drug delivery systems by using a composition containing highly swellable polymers in admixture with a gas-generating agent to form systems that are large in size as well as capable of floating on gastric fluids. It has now become well recognized by those particularly skilled in the art that systems containing swellable polymers will instantly float on gastric fluids because the gas generated and entrapped within the system decreases the density. Swelling to a large size is an important factor in gastric retention of the system. Solids having a size less than 5 to 7 mm show delayed gastric emptying in fed conditions but they can still be emptied from the stomach because their size is smaller than the pyloric sphincter. Even floating systems of size less than 5 to 7 mm can be emptied if the patient is in supine position. The mean resting pyloric diameter is approx. 13+7 mm and it has been reported that dosage forms with a size of approx. 12-18 mm diameter in their expanded state would generally be excluded from the passage of the pyloric sphincter. The system should also be capable of retaining this size in the gastric fluids for long periods under agitational conditions created by gastric motility. Such large intact systems cannot be emptied until the arrival of the interdigestive migrating motor complex at the beginning of the interdigestive phase. The combination of increase in size and floatation results in increased gastric retention of the system. The prior art resulting in this current state of the art is described below.
(A) Swellable Gastric Retention Floating Matrix Drug Delivery Systems
The term “swellable gastric retention floating matrix drug delivery system” herein refers to systems that comprise a drug and an excipient in admixture or in a matrix which is not coated with a polymer coating or not placed inside a polymer envelope or a pouch, and is capable of swelling and floating. Representative prior art illustrating the development of this type of systems is described below.
U.S. Pat. No. 4,777,033 ('033 patent, priority date Jun. 11, 1985) assigned to Teijin Limited, discloses an oral sustained release pharmaceutical preparation comprising a lower alkyl ether of cellulose, polyacrylic acid or its pharmaceutically acceptable salt, a drug, and an effective amount of effervescent foaming agent. Tablets made from the composition however still retained major disadvantages in that the tablets did not remain intact when subjected to dissolution testing. The disintegrated tablet thus does not attain or maintain a size suitable for long duration of retention in the stomach. This prior art presented the problem that if a large amount of gas generating agent, such as sodium bicarbonate, is used in order to sufficiently reduce density and maintain the lowered density for sufficient length of time for achieving floatation of the system, then tablets formed from the same disintegrated.
U.S. Pat. No. 5,651,985 ('985 patent, priority date Feb. 28, 1994) assigned to Bayer AG, claims a pharmacologically active composition comprising a pharmacologically active compound dispersed in a homogenous mixture on the molecular level of polyvinylpyrrolidone and a methacylic acid polymer having an acidic number between 100 and 1,200 mg of KOH/g of polymer solid substance, and optionally a gas-forming additive. With the use of gas-forming additive, the density of the system was reduced on gas generation and the systems were capable of floatation in aqueous medium. The tablets did not disintegrate in an aqueous medium and exhibited marked swelling and high dimensional stability in the swollen state. This dimensional stability was attributed to the non-erodible matrix used in the system. However, the system used relatively low quantities of gas generating agent relative to the '033 patent, and it is not known if the dimensional stability of the system can be maintained when higher quantities of the gas generating additive are used.
U.S. Pat. No. 5,783,212 ('212 patent, priority date Feb. 2, 1996) assigned to Temple University claims a controlled release pharmaceutical tablet comprising a first barrier layer comprising a first swellable, erodible polymer, a drug layer comprising a second swellable, erodible polymer, and a second barrier layer comprising a third swellable, erodible polymer, wherein said first and second barrier layers are adapted to swell and to erode faster than said drug layer; said faster swellability and erodibility of said first and third layers adapted to increase drug delivery from the onset of dissolution. The patent also covers systems wherein at least one of said layers includes a gas-evolving material, which helps the system to float and increases the time of retention of the tablet in the stomach. The patent includes examples wherein the multilayered tablets are obtained by compression and the gas-evolving layer contained relatively larger quantity of the gas-generating agent. All tablets were found to float within about 15 minutes. The examples used polyethylene oxide (PEO) as polymer. Whereas the PEO could retain larger quantity of gas generated by the larger amount of gas generating agent used, the limitation was that the patent exemplified only one polymer that could do so.
U.S. Pat. No. 6,261,601 ('601 patent, priority date Sep. 17, 1997) assigned to Ranbaxy Laboratories used superdisintegrants in the composition. Superdisintegrants are known to swell to several times their volume, their swellability being superior to conventional hydrogel forming swellable polymers such as those used in the '033 patent. The pharmaceutical composition claimed in the patent comprises a drug, a gas-generating component, a swelling agent, a viscolyzing agent, and optionally a gel-forming polymer. The gas generating agents used were carbonates or bicarbonates. The system used viscolyzing agents to prevent disintegration of the system. The drawback of the system was that in order to prevent disintegration of the system, the amounts of superdisintegrant, viscolyzing agent and gas generating agent were required to be optimized. Simultaneously, it was also required that the amounts of excipients be such that the system acquires buoyancy immediately, attains a large expanded size immediately and maintains these characters for sufficient time over which gastric retention is desired. Achieving all these objectives simultaneously is difficult and the formulator may not always be able to do so. Further, the gellable matrix forms an erodible layer on the surface, whereas the core remains dry. Thus, not all of the gas generating agent in the system reacts with the acid of the system. Hence, the buoyancy of the system is capable of being improved by formulating systems where a significant amount of gas generating agent can react with the acid of the environment.
Other prior art references that utilized swellable gastric retention floatation matrix drug delivery systems include WO 0110419A1, WO 0023045A1, WO 0110417A1, WO 03011255A1 and U.S. Pat. No. 6,861,072.
(B) Gas Generating Composition in an Expandable Polymer Envelope or Pouch:
U.S. Pat. No. 3,786,813 ('813 patent, priority date Dec. 27, 1972) assigned to Alza Corporation, claims a drug delivery device for the controlled and continuous administration of a drug to an environment of use comprising a hollow expandable closed member having therein self-contained means for expanding the member, the member being affixed to drug delivery means for delivering a drug at a controlled rate over the given period of time. The patent exemplifies systems wherein a gas generating compartment is connected to a balloon such that the gas generated upon contact with the gastric environment causes the balloon to expand, thereby causing the system to float.
U.S. Pat. No. 4,207,890 ('890 patent, priority date Jan. 4, 1977) assigned to McNeilab, claims a drug dispensing device for controlled and prolonged internal administration of a drug comprising (a) a collapsed, expandable, imperforate envelope made of a substantially non-hydratable, body fluid permeable, drug-permeable polymer film; (b) drug metering means containing said drug and retained by said polymer envelope, whereby drug is dispensed at a predetermined rate; and (c) an effective expandable amount of an expandable agent contained within said polymer envelope, the combination of which agent and which drug when in contact with body fluids cause said polymer envelope to expand to a volume such that the device is retained in the environment of use for at least the minimum desired time. The patent claims systems wherein the polymer film is not applied directly onto the surface of the drug-containing core, but is present in the form of an envelope.
U.S. Pat. No. 4,996,058 ('058 patent, priority date Sep. 18, 1987) assigned to Ciba-Geigy Corporation relates to a dosage form consisting of a sachet which is film coated or filled into capsules, the sachet containing a component that expands on contact with gastric juice and an agent capable of releasing carbon dioxide or nitrogen. The patent does not disclose an expandable coating formed by applying a coating composition comprising a film forming polymer and an expandable component on the surface of a tablet or capsule core, or a method for applying such a coating composition on the surface of a tablet or capsule core. We have found that coating compositions using film forming polymer alone when coated on to tablet or capsule cores of the present invention do not provide desirable floatation, swelling and/or integrity of the system.
U.S. Pat. No. 6,290,989 ('989 patent, priority date Jan. 14, 1997) assigned to LTS Lohmann Therapie-Systeme AG, claims device for the controlled release of active compounds in the gastrointestinal tract with delayed pyloric passage, which device is an improvement over the device of the '890 and '058 patents. The '890 and '058 patents did not provide advice on how the release rate of active compound is to be controlled independently of the permeability of the polymer film forming the sachet. The '989 patent teaches that the active compound can be incorporated in the form of multiparticulates whose nature and composition provides a means for controlling the rate of release of the active compound. Multiparticulates could be present inside the sachet or embedded in the film forming the sachet.
PCT publication number WO 9959637 ('637 patent, priority date May 18, 1998) assigned to LTS Lohmann Therapie-Systeme AG, relates to a device for the controlled release of active agents in the gastrointestinal tract with a prolonged pylorus passage in the form of a bag which expands when the gas generating component of the system generates gas upon contact with gastric juice. The bag is constructed with a polymer membrane made of a monolayered film which controls the release of an active agent located therein, and thus the system has the drawbacks associated with the systems of the '890 and '058 patents, namely, that the release of the active ingredient cannot be controlled independently of the permeability of the polymer film forming the sachet.
U.S. Pat. No. 6,776,999 ('999 patent, priority date Oct. 30, 1998) assigned to LTS Lohmann Therapie-Systeme AG, claims a swallowable, gastroretentive device, which delays passage of the device through the pylorus of the stomach of an orally ingestible pharmaceutical form and releases at least one pharmaceutically active compound in a controlled manner, said device comprising: (a) a pharmaceutical form which contains at least one pharmaceutically active compound; (b) an expandable component which generates gas on contact with gastric juice; and (c) a polymeric membrane system which totally encompasses components (a) and (b) above and is expandable by the gas generated by (b) upon contact with the gastric juice, whereby the polymeric membrane system comprises at least one member selected from the group consisting of a microporous membrane, a porous membrane and a combination of any of the foregoing with a non-porous polymer film. The patent teaches a device in the form of a sachet, which for the purposes of facilitating administration and handling, can be filled into a container made of physiologically acceptable material, for example into hard gelatin capsules.
PCT publication number WO 04032906A1 ('906 patent, priority date Oct. 11, 2002) assigned to DepoMed Development Limited, claims a gastro-retentive dosage form of levodopa for oral administration to a patient in need thereof, said dosage form comprising (a) a tablet comprising a therapeutically effective amount of levodopa, a binder, and a pharmaceutically-acceptable gas-generating agent capable of releasing carbon dioxide upon contact with gastric juice, and (b) an expandable, hydrophilic, water-permeable and substantially gas-impermeable, membrane surrounding the tablet, wherein the membrane expands as a result of the release of carbon dioxide from the gas-generating agent upon contact with the gastric juice, whereby the dosage form becomes too large to pass into the patient's pyloric sphincter. Although the application claims systems wherein the drug-containing core tablet is covered by an expandable, gas-impermeable membrane, the description and examples include systems wherein the drug-containing tablet is introduced into a sachet or pouch made of an expandable, gas-impermeable polyvinyl alcohol membrane. The patent application does not disclose an expandable coating formed by applying a coating composition comprising a film forming polymer and an expandable component on the surface of a tablet or capsule core, or a method for coating such a composition on the surface of a tablet or capsule core.
(C) Gas Generating Composition Coated with Polymer Film:
U.S. Pat. No. 4,101,650 ('650 patent, priority date Apr. 6, 1977) assigned to Zaidan Hojin Biseibutsu Kagalu Kenlcyu Kai discloses a formulation in which granules containing sodium bicarbonate, lactose and polyvinylpyrrolidone are coated with a layer of hydroxypropyl methylcellulose. These are then further coated with a suspension containing the active ingredient pepstatin and hydroxypropyl methylcellulose to form floating minicapsules of a diameter in the range of 0.1 to 2 mm. The drawback of this system is that the minicapsules are much smaller in size than required for long durations of retention in the stomach. Further, the hydroxypropyl methylcellulose layer on the granules is not an expandable polymer film but a film that gels on contact with an aqueous medium.
U.S. Pat. No. 4,844,905 ('905 patent, priority date Feb. 24, 1986) assigned to Eisai Co. discloses granules comprising a drug containing core; a middle gas-generating layer comprising sodium carbonate and organic acid; and an outer coat of an expandable polymer film. Although intended for remaining in the stomach, the granules have the disadvantage of small size. Whereas the coating on the granules works to provide floating granules, we found that when these coatings were used on a tablet or capsule core, the system did not float and the coating disintegrated.
U.S. Pat. No. 6,284,271 ('271 patent, priority date Jul. 1, 1997) assigned to Astrazeneca AB, claims an effervescent dosage form comprising, as a first component, effervescent excipients and as a separate second component, a plurality of individual units comprising a pharmaceutically active compound and optionally pharmaceutically acceptable excipients wherein each unit is provided with a floating generating system comprising at least two coating layers, one of which is a gas generating layer and the other layer is a barrier layer enclosing the generated gas, and wherein the first component is separated from the second component by the layers of the floating generating system. The patent exemplifies dosage forms wherein pellets comprising a core comprising the active ingredient were coated with an inner gas generating layer and an outer hydrophobic polymer layer, followed by mixing of the coated pellets with effervescent excipients and compression into a tablet dosage form. The patent does not disclose an expandable coating formed by coating a composition comprising a film forming polymer and an expandable component on the surface of a tablet or capsule core, or a method for coating such a composition on the surface of a tablet or capsule core.
None of the prior arts described above disclose or teach a gastric retention drug delivery system wherein a tablet or a capsule core is coated with an expandable coating, or teach a method of preparing such a system using suitable coating compositions. We have surprisingly found systems wherein a tablet or capsule core comprising an agent capable of generating internal pressure are coated with a coating composition comprising a film-forming polymer and one or more expandable components.